The long range goal of this project is to study the oxidation of chemicals to toxic metabolites by prostaglandin synthetase (PGS) and to demonstrate the significance of this system in chemical-induced toxicity or carcinogenesis. We have shown that PGS converts both polycyclic hydrocarbons and aromatic amines to mutagens as measured by bacterial tester systems. Other in vitro studies show the formation of electrophilic metabolites that react with macromolecules. Benzo(a)pyrene-7,8-diol is metabolized to anti-diol epoxide by PGS. We have compared PGS and NADPH-dependent metabolism in hamster trachea and human bronchial explants. In both tissues, stimulation of PGS increases anti-diol epoxide formation. The aromatic amine carcinogen, 2-aminofluorene is metabolized to free radical intermediates by PGS. The stable end product are azo- and nitro-fluorene. Our studies indicate that PGS activates chemicals to ultimate carcinogenic metabolites which may be of importance in initiation of tumors in extra hepatic tissue. Thus PGS is an additional enzyme system to cytochrome P-450 in the metabolism of chemicals.